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Ionotropic Therapy in Acute Heart Failure

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1 Ionotropic Therapy in Acute Heart Failure
Dr Sajeer K T Senior Resident Dept of cardiology, MCH ,Calicut

2 AHFS Definition Acute heart failure syndromes (AHFS) are defined as gradual or rapid changes in signs and symptoms of heart failure (HF) that require urgent therapy 1. New-onset or de novo HF ( 20%): (HF stage A & B) - present first time with symptoms of HF - have risk factors for HF/structural heart disease 2. Worsening chronic HF (80%): - history of chronic HF & present with an episode of decompensation (stage C) - 10% to 15% has advanced or end-stage HF (stage D)

3 A practical approach to differentiating AHFS:
- relies on systolic BP at the time of presentation 1.Hypertensive group : - female - normal LVEF - in hospital mortality rate - 2% (with 5% mortality and 30% readmission rates with in 60–90 days of discharge) 2.Normotensive group: - low LVEF - signs and symptoms of pulmonary/systemic congestion (oedema) before and at the time of admission - in-hospital mortality rate - 3% (with 7% mortality and 30% readmission rates within 60–90 days of discharge) 3. Hypotensive group: - low SBP levels (≤120 mm Hg) at the time of presentation - low LVEF history of HF ( mortality rate 7% during hospitalization & with 14%mortaliy and 30% readmission rates within 60–90 days of discharge)

4 Current and investigational pharmacologic agents for the treatment of AHFS

5 Clinical stratification and treatment
Stevenson and colleagues developed an approach for the evaluation and treatment of decompensated advanced chronic systolic heart failure Based on assumption that hemodynamic abnormalities are the immediate cause of the symptoms and signs of AHF by addressing these derangements5→ pts improve symptomatically -Patient is assigned to one quadrant of a 2 × 2 table, defined by the presence or absence of congestion (wet or dry) and low perfusion (cold or warm)

6 Mechanisms of Action and Effects of Inodilators
Common pathway - increased intracellular (cAMP) and calcium concentrations Dobutamine ( beta agonist) Dopamine ( catecholamine) Milrinone (PDE inhibitor) Levosimendan: - Calcium sensitizer - ATP-dependent K+ channel opener Intracellular cAMP causes release of ca2+ from the SR. Calcium →used by contractile proteins Increased stroke volume.

7 Mechanisms of Action and Effects of Inodilator contd..
Dobutamine: Dobutamine ↑ cAMP production: - by beta-adrenergic-mediated stimulation of adenylate cyclase - stimulates cAMP production Dobutamine is a racemic mixture that stimulates beta1- and beta 2-receptors

8 Simplified schematic of postulated intracellular actions
of beta -adrenergic agonists

9 Beta 1-receptors stimulation
Activates guanine nucleotide regulatory cascade (via G proteins) Increased adenylate cyclase activity ATP → increased cAMP Release of calcium from the sarcoplasmic reticulum - Calcium is used by contractile proteins - increased stroke volume

10 Rate of infusion doses of Dobutamine needed to increase
cardiac output usually ranges from 2.5 to 15 µg/kg/min. Onset of action is within 1 to 2 minutes plasma half-life of Dobutamine - 2 minutes. - Infusion for 24 to 72 hours- - cardiac output return toward baseline values (raising the concern of pharmacologic tolerance with prolonged infusion) - Overall effect of dobutamine on BP is variable - depends on the relative effects on the vascular tone and cardiac output achieved Heart rate is often decreased because of reflex withdrawal of sympathetic tone in response to improved cardiovascular function

11 - Major side effects of Dobutamine:
- tachycardia( in patients with AF and atrial and ventricular arrhythmia Patients taking a beta blocker may have an attenuated initial response to Dobutamine until the -blocker has been metabolized Increased energy demands of the failing myocardium lead to a state of relative energy depletion (through an initial compensatory phase of increased oxygen extraction) inodilator stimulation would impose further energy demands and ultimately accelerate myocardial cell death

12 Dopamine—endogenous catecholamines
Dose-dependent effects <2µ g/kg per min: (vasodilation) - by direct stimulation of dopamine postsynaptic type 1 and presynaptic type 2 receptors in the splanchnic and renal arterial beds - direct effects on renal tubular epithelial cells → natriuresis 2 to 5µ g/kg per min – (increased HR and cardiac output) - direct stimulation of beta-adrenergic receptors in the heart induce NE release from vascular sympathetic neurons 5 - 15µ g/kg per min- (↑ed HR and peripheral vasoconstriction) - stimulate beta and alpha-adrenergic receptors

13 Schematic representation of postulated mechanisms
of intracellular action of alpha 1-adrenergic agonists

14 Major side effect of dopamine – tachycardia
(More pronounced with dopamine than Dobutamine) A new or unexplained tachycardia or arrhythmia in a patient receiving “low-dose” dopamine - suspect inappropriately high dopamine infusion rate

15 Milrinone—phosphodiesterase inhibitors
- Selectively inhibits phosphodiesterase (PDE) III ( enzyme that catalyzes the breakdown of cAMP) - increased cAMP Increased intracellular calcium concentration and myocardial contractility as well as acceleration of myocardial relaxation Increased cAMP peripherally produces vasodilation (both the arterial and venous circulation) decreased SVR and PVR decreased left and right ventricular filling pressures - increased cardiac output

16 Milrinone Dosage: - ± loading dose of 50µg/kg per min - continuous infusion of between 0.25 and 1.0µ g/kg per min Improvement in hemodynamic function occurs in 5 to 15 minutes after initiation of therapy Side effect of Milrinone: - hypotension ( avoid loading dose) - Non sustained VT

17 The HFSA 2006 Comprehensive HF Practice Guideline (Dobutamine and Milrinone)
Intravenous inotropes (Dobutamine or Milrinone) may be considered to relieve symptoms and improve end-organ function in patients with advanced HF characterized by - L V dilation - reduced LVEF - diminished peripheral perfusion or end-organ dysfunction (low output syndrome) - systolic blood pressure < 90 mm Hg - have symptomatic hypotension despite adequate filling pressure - unresponsive to, or intolerant of, intravenous vasodilators

18 Dual mechanism of action:
Levosimendan Dual mechanism of action: (1) Enhances calcium myofilament responsiveness by binding to cardiac troponin C increases contraction (functions as a calcium sensitizer) (2) it opens KATP channels in myocytes & SM cells act as a vasodilator ( anti-ischemic and antistunning effects) Levosimendan increases calcium myofilament responsiveness by directly affecting contractile proteins to increase contractility without increasing intracellular calcium concentrations

19 key differentiating property of levosimendan
does not increase intracellular levels of cAMP or calcium does not cause increased myocardial oxygen consumption Opens KATP channels in myocytes and vascular SM cells - results in vasodilatation and cardio protection - reduces preload and after load - increased blood flow to organs (including increased coronary blood flow) - anti-ischemic and antistunning effects Loading dose µ g/kg applied over 10 minutes Continuous infusion to 0.2 µg/kg per min over 24 hours

20 Role of intravenous inotropes therapy in AHF
- a subject of controversy - lack of prospective, placebo controlled trials - lack of alternative therapies

21 Clinical characteristics of patients with acute heart failure syndromes in clinical registries
Acute Decompensated Heart Failure National Registry (ADHERE) Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE- HF) Euro Heart Failure Survey (EHFS) EFICA French study

22 Use of Inodilator Therapy in Acute Heart Failure Syndromes- Registries
ADHERE database (Oct ) : Designed to study prospectively the outcomes, characteristics, and management of AHFS. >150,000 patients - 50% presented with PSF <3% presented with a systolic BP of 90 mm Hg 14% of the patients in ADHERE - treated with ≥1 acute infusions of inodilator agent (Dobutamine 6%, Dopamine 6%, and Milrinone 3%) Patients with PSF who were treated with Inodilators had a higher mortality rate than patients with PSF who were not treated with Inodilators (19% v/s 2% respectively).

23 European Heart Journal Supplements (2005) 7 (Supplement B), B13–B19

24 - longer length of hospital stay (mean: 12.9 v/s. 9.6 days P =0.0001)
Analysis of ADHERE data provides evidence that patients with PSF may respond differently to treatment with positive inotropes compared with those with impaired LVEF Subgroup analysis in patients with PSF who received ionotropic agent showed - longer length of hospital stay (mean: 12.9 v/s. 9.6 days P =0.0001) - higher mortality rate (19 v/s. 14% P = 0.002) Key issues highlighted by ADHERE - Many patients with no apparent clinical indication received positive inotropes, even though these drugs are associated with increased mortality European Heart Journal Supplements (2005) 7 (Supplement B), B13–B19

25 Trials: Intravenous Inodilator Therapy
Regimens of intravenous inodilator therapy: - Short-term therapy: - infused over several hours to a few days in combination with diuretics - discontinued when patients are clinically stable - - Intermittent intravenous therapy: - 4- to 6-hour pulse infusion for several days per /wk or as a single 24- to 72-hour infusion once weekly - Continuous intravenous infusions:

26 Short-Term Use of Inodilator Treatment -Dobutamine v/s Levosimendan
Levosimendan V/s Dobutamine: - LIDO trial - CASINO trial - SURVIVE –W trial

27 Levosimendan Infusion versus Dobutamine (LIDO) study

28 Kaplan–Meier survival analysis in the LIDO
The prospective benefit observed at 31 days for Levosimendan-treated patients was maintained through the 180-day follow-up period.

29 Calcium Sensitizer or Inotrope or None in Low-Output Heart Failure Study (CASINO)
enrolled 600 patients hospitalized with NYHA class IV HF randomized to Levosimendan, Dobutamine, or placebo 48 hrs after presentation primary end point of the study was mortality at one month, 6 months, or 1 yr Dobutamine was associated with lower 6-month survival compared with Levosimendan or placebo in patients with decompensated low output HF Heart Failure Update 2004 and Eur J Heart Fail

30 Survival curves for the three treatment arms of the CASINO study
before complete follow-up of patients

31 Survival of Patients with Acute Heart Failure
in Need of Intravenous Ionotropic Support (SURVIVE)trial JAMA. 2007;297:

32 Trials: Intravenous Inodilator Therapy
Intermittent intravenous therapy : Dobutamine v/s placebo trials


34 - large-scale, placebo-controlled, double-blind study
Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy Versus Placebo in the Short-Term Treatment of Decompensated Heart Failure (REVIVE) - large-scale, placebo-controlled, double-blind study - in 600patients hospitalized for AHFS with LVEF <0.35 & dyspnea at rest who required intravenous diuretics Randomized to receive either Levosimendan or placebo in addition to standard therapy REVIVE-1 data ( n=100) - Levosimendan treatment A/W - improvement in the composite end point at 24 hrs and 5 days - a significant reduction in BNP levels at 24 hours and 5 days - shorter lengths of initial hospitalization


36 LEVOSIMENDAN Randomized Study on Safety and Effectiveness of Levosimendan in Patients with Left Ventricular Failure Due to an Acute Myocardial Infarction (RUSSLAN)

37 Randomized Study on Safety and Effectiveness of Levosimendan in Patients with Left Ventricular Failure Due to an Acute Myocardial Infarction (RUSSLAN)

38 Kaplan–Meier survival analysis in the RUSSLAN trial
The prospective survival benefit of Levosimendan compared to placebo at 14 days were maintained through 180 days of follow-up

39 ESC 2005 guideline on acute HF: Levosimendan
indicated in patients with symptomatic low COP HF secondary to cardiac systolic dysfunction without severe hypotension class IIa/ Level of evidence B

40 Milrinone

41 Short-Term Use of Inodilator Treatment- Milrinone
OPTIME-CHF investigators: - randomized 949 patients (mean age- 65 years) - patients with an exacerbation of systolic HF with NYHA class III to IV HF and an LVEF <0.40 (mean LVEF, 0.23) - studied the effect of short-term Milrinone infusion (48 to 72hrs) - primary outcome: - cumulative days of hospitalization within 60 days of randomization - secondary outcomes: -adverse events and mortality



44 Kaplan-Meier survival curves for in-hospital survival to 60 days by heart failure etiology and treatment assignment in a post hoc analysis of the OPTIME-CHF trial. (Adapted from J Am Coll Cardiol)



47 Dopamine:

48 Dopamine: No randomized controlled trials studying the effects of short-term, intermittent, or long-term continuous infusion of dopamine According to the ESC guideline on acute HF: Dopamine may be used as an Inotrope (2µ g/kg per min ) - acute HF with hypotension. Infusion of low doses of dopamine (2–3 µg/kg per min) - used to improve renal blood flow and diuresis in decompensated HF with hypotension and low urine output ( if no response is seen→ the therapy should be terminated -(class IIb)

49 Digoxin in Acute Heart failure

50 Digoxin in Acute Heart failure
Digoxin has been used in patients with Chronic HF for >200yrs - it remains an important agent in the modern era - its role in the treatment of acute HF is unclear In a study involving 6 patients with acute MI with HF →IV Digoxin v/s Dobutamine Digoxin - no effect on LV filling pressure - slight effect on cardiac index & stroke work index (in contrast to marked favorable hemodynamic effects produced by IV dobutamine)

51 - NEJM 1980;303:846–850.

52 - increased stroke work index.
Comparative Hemodynamic and Neurohormonal Effects of IV Captopril and Digoxin and Their Combinations in Patients With Severe Heart Failure In 16 patients with severe HF and sinus rhythm, the effects of acute administration IV Digoxin and IV Captopril on rest and exercise hemodynamics were studied Digoxin and Captopril were given separately and in combination both at rest and during maximal exercise Digoxin - decreased PCWP - increased stroke work index. Digoxin in combination with Captopril resulted in - further decrease in PCWP - further increase in stroke work index - JAAC1989;13:134-42)

53 ↓in PCWP – by captopril – 24% by digoxin - 34% (p = 0.004)
Comparative Hemodynamic and Neurohormonal Effects of IV Captopril and Digoxin and Their Combinations in Patients With Severe Heart Failure - JAAC1989;13:134-42) When given separately ↓in PCWP – by captopril – 24% by digoxin % (p = 0.004) ↓SVR - by captopril 23% (p = 0.09) - by dogoxin 20% (p = 0.03) Only Digoxin increased - cardiac index by 23% (p = 0.03) - stroke work index by 52% (p = 0.01)

54 - the effects of Digoxin on clinical outcomes in patients
Despite the beneficial hemodynamic and neurohormonal effects and long-term safety data - the effects of Digoxin on clinical outcomes in patients with AHFS is not well studied ACC/AHA 2005 guideline on chronic HF : “Digoxin is not indicated as primary therapy for the stabilization of patients with an acute exacerbation of HF symptoms, including fluid retention or hypotension.” HFSA 2006 Comprehensive HF Practice Guideline ESC 2005 guideline on acute HF - do not address Digoxin

55 Istaroxime in acute heart failure

56 Istaroxime in acute heart failure
- Positive inotropic + positive lusitropic properties - Inhibit sarcolemmal Na-K ATPase → cytosolic Ca accumulation→ +ve inotropism Stimulate SR calcium ATPase → rapid sequestration of cytosolic calcium into the SR during diastole → Promotes myocardial relaxation (lusio) improves myocardial contractility, hemodynamics, LVEF Improves diastolic relaxation in the absence of pro arrhythmic or ischemic effects

57 Change in pulmonary capillary wedge pressure
HORIZON-HF Trial design: Patients admitted with acute decompensated HF were randomized to istaroxime, an inotropic and lusitropic agent (n = 89), versus placebo (n = 31). (p = 0.048) (p = 0.001) Results Change in E’ velocity: 0.5 cm/sec for istaroxime vs cm/sec for placebo (p = 0.048) Change in pulmonary capillary wedge pressure: -3.7 mm Hg vs mm Hg (p = 0.001), respectively Cardiac index: 0.12 L/min/m2 vs L/min/m2 (p = 0.57), respectively 0.5 -0.2 mm Hg cm/sec Conclusions Istaroxime may be beneficial in improving hemodynamics and diastolic function in patients with acute decompensated HF. Future studies are needed to address the impact on clinical outcomes from this agent. -3.7 -0.7 Change in pulmonary capillary wedge pressure Change in E’ velocity Istaroxime Placebo Shah SJ, et al. Am Heart J 2009;Apr24:[Epub]

58 ESC HF Guidelines-2012 - inotropes dosage recommended

59 Recommendations for inotropes in AHF
ESC HF Guidelines-2012 Recommendations for inotropes in AHF

60 summary Conventional inotropes (Dobutamine, dopamine, Milrinone) can rapidly improve hemodynamic parameters in patients with AHFS/LO - Benefits may be offset by risks of adverse effects including increased myocardial oxygen demand and excessive intracellular accumulation of calcium → arrhythmogenic & promote cell death role of IV Digoxin remains to be determined Development of drugs that improve contractility without producing calcium overload represents an important but unaccomplished goal in the management of patients with AHFS/LO.

61 CONCLUSION Use of current intravenous inotropes has been a/w risk for
- hypotension - atrial and ventricular arrhythmias - increased post discharge mortality There is an unmet need for new agents to safely improve cardiac performance (contractility and/or active relaxation) in this patient population.

62 Thank you

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